Compounds which are inhibitors of HIV protease are useful for inhibiting HIV protease in vitro and in vive and are useful for inhibiting an HIV infection. Certain HIV protease inhibitors comprise a moiety which is a substituted 2,5-diamino-3-hydroxyhexane. HIV protease inhibitors of particular interest are compounds of the formula 1: ##STR5## wherein A is R.sub.2 NHCH(R.sub.1)C(O)-- and B is R.sub.2a or wherein A is R.sub.2a and B is R.sub.2 NHCH(R.sub.1)C(O)-- wherein R.sub.1 is loweralkyl and R.sub.2 and R.sub.2a are independently selected from --C(O)--R.sub.3 --R.sub.4 wherein at each occurrence R.sub.3 is independently selected from O, S and -N(R.sub.5)-- wherein R.sub.5 is hydrogen or loweralkyl and at each occurrence R.sub.4 is independently selected from heterocyclic or (heterocyclic)alkyl; or a pharmaceutically acceptable salt, prodrug or ester thereof. Compounds of formula 1 are disclosed in European Patent Application No. EP0486948, published May 27, 1992.
A preferred HIV protease inhibitor of formula 1 is a compound of formula 2a: ##STR6## or a pharmaceutically acceptable salt, prodrug or ester thereof.
Another preferred HIV protease inhibitor of formula 1 is a compound of formula 2b: ##STR7##
The compound of formula 2b is disclosed in PCT Patent Application No. WO94/14436, published Jul. 7, 1994, which is hereby incorporated herein by reference.
An intermediate which is especially useful for preparing compounds of the formula 1 and 2 is a substantially pure compound of the formula 3: ##STR8## wherein R.sub.6, R.sub.7 and R.sub.8 are independently selected from hydrogen and an N-protecting group; or an acid addition salt thereof. Preferred N-protecting groups R.sub.6 and R.sub.7 are independently selected from ##STR9## wherein R.sub.a and R.sub.b are independently selected from hydrogen, loweralkyl and phenyl and R.sub.c, R.sub.d and R.sub.e are independently selected from hydrogen, loweralkyl, trifluoromethyl, alkoxy, halo and phenyl; and ##STR10## wherein the naphthyl ring is unsubstituted or substituted with one, two or three substitutents independently selected from loweralkyl, trifluoromethyl, alkoxy and halo.
Alternatively R.sub.6 and R.sub.7 taken together with the nitrogen atom to which they are bonded are ##STR11## wherein R.sub.f, R.sub.g, R.sub.h and R.sub.i are independently selected from hydrogen, loweralkyl, alkoxy, halogen and trifluoromethyl.
In addition, R.sub.7 can be R.sub.7a OC(O)--wherein R.sub.7a is loweralkyl (preferably, t-butyl) or benzyl.
More preferred N-protecting groups R.sub.6 and R.sub.7 are those wherein R.sub.6 and R.sub.7 are independently selected from benzyl and substituted benzyl wherein the phenyl ring of the benzyl group is substituted with one, two or three substituents independently selected from loweralkyl, trifluoromethyl, alkoxy, halo and phenyl. The most preferred N-protecting groups R.sub.6 and R.sub.7 are those wherein R.sub.6 and R.sub.7 are each benzyl.
Preferred N-protecting groups R.sub.8 are --C(O)R" wherein R" is loweralkyl, alkoxy, benzyloxy or phenyl wherein the phenyl ring is unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, trifluoromethyl, alkoxy and halo. A most preferred N-protecting group R.sub.8 is t-butyloxycarbonyl.
Preferred intermediates of the formula 3 are the compounds wherein (i) R.sub.6, R.sub.7 and R.sub.8 are each hydrogen or (ii) R.sub.6 and R.sub.7 are each benzyl or substituted benzyl wherein the phenyl ring of the benzyl group is substituted with one, two or three substituents independently selected from loweralkyl, trifluoromethyl, alkoxy, halo and phenyl, or R.sub.6 and R.sub.7 taken together with the nitrogen atom to which they are bonded are ##STR12## wherein R.sub.f, R.sub.g, R.sub.h and R.sub.i are independently selected from hydrogen, loweralkyl, alkoxy, halogen and trifluoromethyl and R.sub.8 is hydrogen or t-butyloxycarbonyl or (iii) R.sub.6 and R.sub.7 are hydrogen and R.sub.8 is t-butyloxycarbonyl.